title: Dual topology of functional Toll-like receptor 3 expression in human hepatocellular carcinoma: differential signaling mechanisms of TLR3-induced NF-kappaB activation and apoptosis.
abstract: Toll-like receptor 3 (TLR3) is a pattern-recognizing receptor that is involved in immune signaling and plays a crucial role in survival by being able to recognize various viral components including double-stranded RNA (dsRNA). TLR3 expression and function in cancer cells are not well understood. We investigated the expression of TLR3 in hepatocellular carcinoma (HCC) cells and the function of TLR3 signaling by stimulation and transfection with polyinosinic-polycytidylic acid (Poly I:C), a synthetic form of dsRNA. TLR3 mRNA was expressed in HCC tissues as well as in non-tumor tissues. Positive immunohistochemical staining for TLR3 was observed in 52.7% of HCC tissues, and in HCC cells we found both membranous and cytoplasmic expression of TLR3. While cell surface stimulation of TLR3 with Poly I:C did not affect cell viability, it did activate NF-kappaB levels. In contrast, cytoplasmic stimulation with transfected Poly I:C significantly induced apoptosis accompanied by the down-regulation of anti-apoptotic protein. Transfected Poly I:C also synergistically augmented TRAIL-induced apoptosis, but only with low levels of transfected Poly I:C was IFN-beta production not observed. In conclusion, our results indicate that TLR3 expression in HCC plays an important role with regard to cell survival and proapoptotic activity. Endogenously expressed TLR3 may provide new clinical prospects for TLR3 agonists as cytotoxic agents in HCC.
authors.affiliation: Department of Gastroenterology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yoneda
authors.forename: Kazushi
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Katsuya
authors.initials: K
authors.lastname: Shiraki
authors.forename: Junichiro
authors.initials: J
authors.lastname: Tanaka
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Beppu
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fuke
authors.forename: Norihiko
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Masuya
authors.forename: Ryo
authors.initials: R
authors.lastname: Horie
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Uchida
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takei
mesh_terms: D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D011070:Poly I-C / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; C495344:TLR3 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D011070:Poly I-C